1. Field of the Invention
Embodiments of the present invention relate in general to the combined use of laser therapy and cytotoxic agents in the treatment of vascular lesions including tumors. More particularly, embodiments of the present invention relate to methods of reducing or eliminating growth of tumors using laser light and bioreductive agents without significant harm to surrounding normal tissue.
2. Description of Related Art
Vascular targeting is an anticancer strategy in which the endothelial wall of the blood vessels supplying the tumor is the treatment target, and tumor cell hypoxia is a therapeutic goal. Because of the interdependence of tumor cells and tumor vasculature, prolonged ischemia secondary to irreversible loss of tumor blood vessel function will result in tumor cell necrosis. Vascular targeting has as its goal the destruction of existing tumor vasculature and so differs from anti-angiogenic therapies aimed at preventing the growth of new vessels within a tumor.
The function of the tumor vascular supply has significance both in the natural progression of a malignancy and in the outcome of treatment. The chaotic vascular architecture and abnormalities of blood flow within tumor microvessels are associated with regions of tumor hypoxia that limit the efficacy of both chemotherapy and radiotherapy. Similarly, the effectiveness of photodynamic therapy depends on an adequate oxygen level within the tumor for generation of cytotoxic species.
The application of phototherapy to tumor treatment has been actively pursued because of both the incidence and health significance of tumors that arise in the skin or mucosal surfaces, including the gastrointestinal tract, aerodigestive tract, urinary bladder, and cervix, and therefore are readily accessible to radiation. The phototherapeutic approach typically involves administering a photosensitizer, allowing a suitable period of time for uptake of this photosensitizer by the tumor tissue, and irradiation at a wavelength absorbed by the photosensitizer to produce cytotoxic species. Although preferential accumulation of photosensitizer in tumor versus normal tissue has been demonstrated for certain photosensitizers, prevention of damage to normal vasculature typically requires spatial confinement of the irradiated zone to the target tumor tissue.
When the photosensitizer is administered intravenously, it has been observed that vascular damage follows irradiation. This vascular damage has been exploited in ophthalmology for treatment of pathologic ocular neovascularization and in dermatology for treatment of benign vascular lesions. Photodynamic therapy specifically designed to target tumor vasculature has been described. However, the mechanism of photodynamic therapy leads to vascular damage in any tissue that is exposed to radiation, in the presence of sufficient oxygen. Tumor blood vessels and the vessels supplying normal tissue surrounding the tumor are both susceptible to damage by the cytotoxic species produced by the intravenous photosensitizer during illumination.
Selective photothermolysis is a method of causing selective and irreversible photothermal damage to tissue structures containing a chromophore that can be used to distinguish that target structure from surrounding tissue. For a light source, typically a laser, to be useful for selective photothermolysis, it must emit with sufficient intensity at a wavelength preferentially absorbed by the target chromophore. The pulse duration or exposure time of the source must be less than the thermal relaxation time of the target, to minimize temperature increases in tissue surrounding the target. Techniques based on this concept using well known laser systems are well established for treatment of benign cutaneous vascular lesions such as portwine stain (PWS), birthmarks, telangiectasias, hemangiomas, warts, psoriasis, arthritis in which hemoglobin in the abnormal, ectatic lesional vasculature serves as the chromophore and the target is the vessel wall, as well as, atherosclerotic plaque and other desired applications. See U.S. Pat. No. 5,312,395; U.S. Pat. No. 5,749,868; U.S. Pat. No. 5,257,970; U.S. Pat. No. 5,066,293, U.S. Pat. No. 5,346,488, "Selective Photothermolysis: Precise Microsurgery by Selective Absorption of Pulsed Radiation", Anderson et al., Science, 220:524-527 (1983); Spears et al. J. Clin. Invest, 71, 39-399 (1983) each of which are hereby incorporated by reference in their entireties for all purposes. The deepest blood vessels contributing to the color of PWS lesions are approximately 1 mm below the skin surface, and are accessible to selective photothermal targeting using available lasers such as the 585 nm pulsed dye laser. The theoretical advantages of selective photothermolysis have been borne out in clinical studies showing that PDL treatment of benign cutaneous vascular lesions is associated with very low risk of scarring. However, photothermolysis techniques would be more effective if the results of damage to surrounding tumor vasculature and other blood vessels primarily responsible for maintaining growth of the tumor could be advantageously used to promote the efficacy of cytotoxic agents which are activated by hypoxic conditions produced as a result of tumor vascular damage.
Accordingly, there is a need in the art to provide methods of treating tumors combining photothermolysis and cytotoxic species that are activated under hypoxic conditions. There is also a further need in the art to selectively localize the effects of photothermolysis to target tumors and their associated microvasculature without significantly harming surrounding normal tissue.